Recent reports indicate that cardiac failure occurs in the absence of coronary vascular disease in patients with diabetes mellitus. Studies are proposed to elucidate the molecular mechanisms which may contribute to the decreased contractility of the heart in diabetes mellitus. In preliminary investigations we have found that the Ca++ activated myosin ATPase activity is decreased by 45% in the heart of diabetic rats. A close correlation between the activity of this enzyme and the velocity of shortening of cardiac muscle has been established. The decrease in enzyme activity is accompanied by a diabetes induced change in the distribution of different components of myosin. The rat ventricle contains three myosin components, myosin V1, V2 and V3. The Ca++ activated myosin ATPase activity of V1 myosin is eight times higher than that of V3 myosin. In normal animals V1 myosin predominates, whereas in diabetic hearts V3 myosin is the predominant form. Preliminary results show that myosin V1 is composed of two identical myosin heavy chain species (MHC-V1), myosin V3 contains two identical heavy chain species (MCH-V3) which are different from MHC-V1 and myosin V2 is composed of one MHC-V1 and one MHC-V3 each. We want to confirm these preliminary results that the myosin components are ture isoenzymes which differ in their myosin heavy chains. In addition we will attempt to clarify the molecular mechanisms which underly the predominant formation of myosin V3 in diabetic hearts. For this purpose the relative synthesis and degradation rates of MHC-V1 and MHC-V3 will be determined in control, diabetic and insulin treated diabetic rats. MHC-V1 and MHC-V3 will be separated by electrophoretic techniques and with the help of specific antibodies. We will also attempt to quantitate the level of MHC-V1 mRNA and MHC-V3 mRNA in an in vitro translational system. These studies will also be performed in rats with diabetes of different degrees of severity. In addition we will investigate which of the diabetes mellitus induced changes in the metabolic milieu may mediate alterations in the predominance of myosin components which occur in the diabetic heart.